Abstract After decades of effort, global campaigns to eradicate poliovirus are nearing completion. Eradiation of wild-type PV-2 has been certified and PV1 and PV2 may be eradicated in the next few years. Many organizations and countries have collaborated in these efforts and are to be congratulated for their dedication and persistence. The oral polio vaccine (OPV) has been the workhorse of mass vaccination efforts because of its low cost and ability to stimulate robust and durable immunity. However, OPV quickly reverts to pathogenic phenotypes in the human and vaccinees secrete wild-type virus that can infect nave bystanders. In addition, the virus can replicate chronically in immune compromised people who can shed virus for many years. For these reasons, OPV is being replaced by the inactivated polio vaccine (IPV) which also stimulates durable immunity. Unfortunately, IPV costs considerably more than OPV per dose ($3-5 vs $0.12 on the subsidized world market). Because the WHO and most countries have plans to continue vaccination for at least 10 years after eradication, there will continue to be a market for the vaccine. Because of the high cost of the IPV, efforts are underway to derive improved and less expensive IPV vaccines. In a Phase 1 SBIR, we tested the feasibility of producing a less expensive IPV using a recently developed radiation-inactivation method. A reconstituted Mn+2-decapeptide phosphate complex (MDP) from the radiation-resistant bacterium Deinococcus radiodurans protects antigenic sites in proteins from oxidative damage at radiation doses that obliterate DNA/RNA genomes of viral and bacterial pathogens. We hypothesized that the new method could increase the antigenicity per unit of starting virus because it avoids the extensive 12 - 28 day formalin incubation that damages the polio antigens by spontaneous protein degradation and cross-linking epitopes. Preservation of antigenicity would increase the number of doses that can be produced per milligram of purified virus and simplification of the inactivation process could reduce costs further. After optimizing the process for inactivating 100% of virus infectivity while protecting the protein capsid, we normalized the irradiated PV2 virus to the D antigen concentrations found in commercial vaccines. Rats immunized with irradiated PV2 developed robust neutralizing titers. A 1/32 fraction of the normal human dose of irradiated PV2 stimulated similar levels of neutralizing antibodies as a 1X dose of the commercial IPV product. We propose to extend these findings to include PV1 and PV3 and then derive a trivalent vaccine having the minimum dose of each component that stimulates equivalent neutralizing antibody levels as IPV. In addition to a reduction in cost, the novel vaccine will have two additional features: the use of attenuated Sabin strains and the development of lyophilization procedures. The transition to Sabin strains will reduce the biohazard risks currently associated with producing large quantities of pathogenic strains. This feature may allow less sophisticated companies or government labs in developing countries to manufacture their own vaccines. In addition, the use of the Sabin strains may improve acceptance of the product due to the reduced risk perception associated with low levels of residual infections virus that may not be detected in quality analysis procedures. The development of a lyophilization process would improve product stability such that the vaccine would not require refrigeration during shipping and may reduce the need for refrigerated storage. In addition, a lyophilized vaccine could be stable for many years when placed in national vaccine stockpiles. We have discussed the findings of the Phase I with several polio vaccine experts and scientists at companies that currently manufacture the vaccine. The results have been met with enthusiasm and interest for future interactions. We will keep the wider community informed of our progress during the Phase II so that we may have partnering options earlier in the development process than originally planned. The main goal of the project is to develop an improved and less expensive inactivated polio vaccine. However, the project will also advance the irradiation technology using a highly characterized virus. The same method could be applied to the rapid and efficient preparation of vaccines against newly emerging pathogens such as Ebola, Zika, and other deadly pathogens. The regulatory pathway derived from the development of a radiation-inactivated PV vaccine would be invaluable when developing vaccines against these less characterized pathogens.